Scripps Florida Scientists Uncover Cellular Process Behind Premature Aging

Newswise, January 3, 2017– December 21, 2016 – In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown how two genes “balance” each other to maintain normal cell function. A disruption in one of the genes, called spns1, can induce degradation and premature “senescence”—or aging—while the other gene, called atp6v0ca, can jump in to suppress that degradation.

Their experiments in zebrafish suggest that these combined genetic disruptions can counteract premature aging and extend developmental lifespan.

“We found that the dual defects did indeed counteract senescence during development and extended the animal’s survival and life span,” said TSRI Associate Professor Shuji Kishi.

The findings, published recently in the journal Autophagy, could also guide future treatments for diseases that involve the body’s inability to degrade unwanted or harmful compounds.

A Closer Look at Lifespan

Cellular senescence is when cells stop dividing and is a normal part of aging. Interestingly, senescence is not only observed in later aging stages but is also detectable during embryonic development in vertebrates.

In the new study, the researchers took a closer look at the gene spns1. In vertebrates, such as zebrafish and humans, the protein encoded by spns1 is important in a cellular process called autophagy, when the cell moves unwanted material to a cellular structure called the lysosome.

Previous research had shown that defects in this gene can also cause senescence in the embryonic stage and premature aging symptoms in adulthood.

However, Kishi and his colleagues found that a concurrent disruption of another gene— atp6v0ca, whose sole defect still causes senescence—led to suppression of the process induced by the defective spns1 gene.

“Our findings suggest that these two defects actually function at a balance point that is critically involved in the regulation of developmental senescence—and that balance allows for normal cell function,” said Kishi.

Restoring the Balance

The scientists are now considering ways to influence the balance between these genes as a strategy to treat lysosomal storage diseases such as Pompe disease, where the excessive buildup of a substance called glycogen results in severe muscle weakness.

They believe there may also be applications in treating age-associated degenerative diseases linked to late-stage autophagy disruption.

“The use of appropriate inhibitors, selective for key steps in the biosynthesis of cellular macromolecules in general, may restore normal dynamics in the autolysosomal compartment and correct the pathological storage that is the ultimate cause of these types of disease,” said TSRI Research Associate Shanshan Lian, the co-first author of the study.

The findings may also lead to the development of tools to help identify new genes that affect the aging process without the need for performing lengthy adult lifespan analyses.

This approach could be applied to the high-throughput identification of pharmacological agents that control aging and lifespan through enhanced resistance to various stressors, including oxygen radicals.

In addition to Kishi and Lian, other authors of the study, “Autolysosome Biogenesis and Developmental Senescence Are Regulated by Both Spns1 and V-Atpase,” include TSRI’s Tomoyuki Sasaki, a co-first author and Alam Khan; Jesse R. Llop, Andrew V. Samuelson of the University of Rochester; Wenbiao Chen of the Vanderbilt University; and Daniel J. Klionsky of the University of Michigan.

This study was supported by the National Institutes of Health (grants GM101508 and GM053396).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

EPIGENETIC CLOCK PREDICTS LIFE EXPECTANCY

UCLA-led study shows 5 percent of population ages faster, faces shorter lifespan

The rate of your biological clock influences how long you'll live.

Why do some people lead a perfectly healthy lifestyle yet still die young? A new international study suggests that the answer lies in our DNA.

Newswise, October 3, 2016 — UCLA geneticist Steve Horvath led a team of 65 scientists in seven countries to record age-related changes to human DNA, calculate biological age and estimate a person’s lifespan. A higher biological age—regardless of chronological age—consistently predicted an earlier death.

The findings are published in today’s edition of the journal Aging.

“Our research reveals valuable clues into what causes human aging, marking a first step toward developing targeted methods to slow the process,” said principal investigator Horvath, a professor of human genetics and biostatistics at UCLA’s David Geffen School of Medicine and Fielding School of Public Health.

Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women’s Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe.

Applying a variety of molecular methods, including an epigenetic clock developed by Horvath in 2013, the scientists measured the aging rates of each individual.

The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood’s biological age, the scientists used the clock to predict each person’s life expectancy.

“We were stunned to see that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans,” said first author Brian Chen, a postdoctoral fellow at the National Institute on Aging.

“This rang true even after adjusting for traditional risk factors like age, gender, smoking, body-mass index, disease history and blood cell counts.”

The group’s findings, however, don’t bode well for everyone.

“We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy,” Horvath said. “Accelerated aging increases these adults’ risk of death by 50 percent at any age.”

For example, two 60-year-old men, Peter and Joe, both smoke to deal with high stress. Peter’s epigenetic aging rate ranks in the top 5 percent, while Joe’s aging rate is average. The likelihood of Peter dying within the next 10 years is 75 percent compared to 60 percent for Joe.

The preliminary finding may explain why some individuals die young – even when they follow a nutritious diet, exercise regularly, drink in moderation and don’t smoke. 

“While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever,” Horvath emphasized. “Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one’s epigenetic aging rate.”

Scientists have long searched to identify biomarkers for biological age, according to coauthor Dr. Douglas Kiel, a professor at Harvard Medical School and a senior scientist for the Institute of Aging Research at Hebrew SeniorLife.

“In geriatric medicine, we are always struck by the difference between our patients’ chronological age and how old they appear physiologically,” said Kiel.

“This study validates the use of DNA methylation as a biomarker for biological age. And if we can prove that DNA methylation accelerates aging, we can devise strategies to slow the rate and maximize a person’s years of good health.”

The precise role of epigenetic changes in aging and death, however, remains unknown, said coauthor Dr. Themistocles Assimes, an assistant professor of cardiovascular medicine at Stanford University School of Medicine.

“Do the epigenetic changes associated with chronological aging directly cause death in older people?” said Assimes.

“Perhaps they merely enhance the development of certain diseases--or cripple one’s ability to resist the progression of disease after it has taken root. Future research is needed to address these questions.”

Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases, he added.

By 2017, according to the World Health Organization, the number of people worldwide over age 65 will outnumber those under age 5 for the first time in recorded history.

By 2050, the proportion of the global population over 60 will double from 11 to 22 percent. Many countries will be ill-prepared to keep pace with the high costs associated with disease and disability as more people live longer, said Horvath.

“We must find interventions that prolong healthy living by five to 20 years. We don’t have time, however, to follow a person for decades to test whether a new drug works.” said Horvath. “The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years.”

The University of California has applied for a provisional patent on the epigenetic clock.